Diamino compounds and process for the production thereof



United States Patent DIAMINO COIVIPOUNDS AND PROCESS FOR THE PRODUCTHONTHEREOF Emil Girod, Riehen, near Basel, and Franz Hiifliger, Basel,Switzerland, assignors, by mesne assignments, to Geigy ChemicalCorporation, New York, N. Y., a corporation of Delaware No Drawing.Application December 6, 1951, Serial No. 260,312

Claims priority, application Switzerland December 12, 1950 6 Claims.(Cl. 260-313) The present invention relates to diquaternary diammoniumcompounds derived from ditertiary amines of the general formula andcorresponding to the following general formula:

In these and all the following formulae By lower dialkylamino radicalsare meant especially those with alkyl groups having from 1-4 carbonatoms. The piperidinoand pyrrolidino radicals, etc. particularly comeinto question as alkylene imino radicals with -6 ring members. In regardto their influence on the chemical and pharmacological properties of theend products they are generally equivalent to the lower dialkylaminoradicals.

Price and Roberts (J. org. Chem. 12, 264-268 (1947)) tested the activityagainst malaria protozoa of 1.2-di-(2-diethylaminoethyl-mercapto)-ethane and 1.2-di-(2'-dibutylamino ethylmercapto)-ethane produced by reacting 1.2-di-(2'-chlorethylmercapto)-ethane with diethyl amine or dibutylamine. These bases hadonly a weak effect.

It has now been found that the new compounds defined above have a veryinteresting pharmacological action in another direction, e. g. on thetonus of the muscles.

The ditertiary amines of the general formula given above can be producedin two different but related ways. Firstly, an alkane dithiole of thegeneral formula:

or a salt thereof can be reacted with 2 mols of a tertiary aminoalkylhalide of the general formula:

with 2 mols of tertiary aminoalkane thioles of the general formula:

(Am)N(CH2)m-SH or with salts thereof.

Patented Jan. 15, 1957 ice In both cases it is advantageous to performthe reaction in the presence of a solvent and a base which binds thehydrogen halide which is split off. It is also advantageous to firstconvert the mercaptan into a salt by means of a base. Suitable basesare, e. g. sodium amide, lithium amide, sodium ethylate, sodiumhydroxide and potassium hydroxide. When using alkali amides, neutralsolvents and those having no hydroxy groups are suitable such as diethylether, dibutyl ether, dioxane, benzene, toluene, xylenes and parafiinhydrocarbons. In addition to these, alcohols such as ethanol and butanolcan be used when working with alcoholates and also water when usingalkali hydroxides. In general, the reactions taken place at moderatetemperatures, i. e. between 0 and C.

To produce compounds with two different tertiary aminoalkyl groups, thereaction may proceed in steps by reacting one mol of an alkane dithioleof the general formula given above first with one mol of a tertiaryaminoalkyl halide and then with one mol of a different tertiaryaminoalkyl halide. Another process is the reaction of one mol of adihalogen alkane with one mol of a tertiary aminoalkane thiol and thenwith one mol of a different aminoalkane thiol.

Any tertiary aminoalkyl mercaptans corresponding to the formula thereforgiven above can be used as starting materials. As examples may belisted: 2-dimethylamino-ethylmercaptan, Z-diethylamino-ethylmercaptan, 2(2'.S' dimethyl pyrrolidino) ethylmercaptan,3-(2-methylpiperidino)-propylmercaptan, and 3-methylethylaminopropylmercaptan. These mercapto compounds can be reacted with anydihalogen alkanes corresponding to the formula therefor given above. Asexamples may be listed: 1.10-dibromo-decane, 1.11-dibromoundecane, and1.12-dibromo-dodecane. On the other hand, any tertiary aminoalkyl halidewhich corresponds to the formula therefor given above, can be reactedwith an appropriate alkane dithiole. As examples may be listed:Z-dimethylamino-ethyl chloride, 2-(methyl-ethylamino)-ethyl chloride,and 2-dipropylamino-ethyl chloride.

The pure bases produced according to this invention are generally in theform of colorless or light colored oils. They form salts with inorganicor organic acids. Some of the bases do not decompose when distilled inthe vacuum and so can be purified; however, the higher molecular'basessuch as 1.10-di-(2'-diethylamino ethyl mercapto)-decane change whendistilled under a pressure of about 0.1 mm. Because of their basicproperties these compounds should be separated from any neutral or acidaccompanying substances and freed from volatile bases by partialdistillation in the vacuum.

The raw products so obtained are sometimes rather strongly colored butare pure enough, however, for many purposes. If desired they may bepurified by filtration through absorption agents such as charcoal,fullers earth, etc., by chromatography or by conversion into salts whichcan form crystals.

A few examples of ditertiary diamines intermediate products producedaccording to the invention are:

To convert these compounds into diquaternary diammonium compounds of theformula given at the beginning, the ditertiary diamines are reacted withabout 2 mols of alkylating agents of the general formula Methyl bromide,methyl iodide, dimethyl sulphate, ethyl bromide, ethyl iodide, propylbromide, allyl bromide, butyl bromide and hexyl iodide are examples ofsuch alkylating agents. If necessary, the reaction is performed in aclosed vessel in the presence or absence of solvents. Either sutficientheat is generated to complete the reaction or the components can begently heat- 20 ed to temperatures not exceeding about 100 C.

As the pharmacological activity of the slats according to this inventiondepend chiefly on the cation, the type of anion is of lesser importancefor the purpose of this invention. Only salts of such inorganic ororganic acids should be used for therapeutical purposes which are not inthemselves strongly toxic and so do not cause pharmacological sideeffects. In other respects, the choice of anion depends on various otherfactors such as cost of acid or of alkylating agent, facility ofreaction, capability to form crystals (possibility of purifying) andwater solubility of the products. The most suitable solution is easy tofind from case to case by a few tests. The anion is an iodine ion in thegreater number of the quaternary salts described below because the alkyliodide is particularly easy to add to the tertiary bases, and becausethe products are often capable of forming crystals and at the same timeare soluble in water. The bromides have the same advantages and inaddition are cheaper. Apart from the addition of alkyl chlorides,dialkyl sulphates and such like, salts with other anions can also beprepared by a double reaction by methods known per so from thequaternary salts obtained by direct addition (e. g. sulphates fromiodides and silver sulphate; Reineckes salts from bromides and Reineckesammonium salt).

The diquaternary salts are almost colourless compounds which crystalliseor sometimes they are in the form of yellow viscous oils. Particularlyorganic solvents or suitable mixtures thereof such as mixtures fromthose which generally dissolve well like alcohols with those which donot dissolve so well such as acetone or ethyl acetate or those which donot dissolve well such as ether or benzene are suitable for theformation of crystals. In general, these salts dissolve well in waterwith a practically neutral reaction.

Of the tliquaternan diammonium compounds derived from polymethylenedithioles with 10 to 12 carbon atoms, the decamethylene dithiolederivates are particularly interesting in View of their muscle-relaxingactivity. The salt of, for instance l.l-bis-(2'-triethyl ammonium ethylthio) -decane has a strong activity similar to that of curare on the ratand rabbit as Well as a considerable spasmolytic action on the isolatedrabbit intestine.

The following compounds are given as examples of diqtiaternary ammoniumsalts:

The following examples serve to illustrate the invention further. Wherenot otherwise stated, parts are always given as parts by weight ingrammes and the relationship of parts by weight to parts by volume isthat of grammes to cubic centimetres. The temperatures are given indegrees Centigrade.

Example 1 (CH2) [SCH2CH2N (CzHs )2]2 A very fine suspension of10.5 partsof sodium amide in abs. toluene is slowly added to 100 parts by volumeof abs. toluene, parts of LIO-dibromodecane and 30 parts of diethylaminoethyl mercaptan in a nitrogen atmosphere at -50". On completion of theaddition, the whole is stirred for 2 hours at 40-50" and then boiled for2 hours under reflux. After cooling, suflicient 2n hydrochloric acid isstirred in to give the solution an acid reaction to congo red, the twolayers are separated and the hydrochloric acid solution which containsthe base is washed with ether. The base is then 'freed by the additionof 30% caustic soda lye. The product is isolated by ethering out,washing of the ether solution with water, drying with potash anddistilling off the ether. Volatile by-products are removed as well aspossible from the raw product by heating to -90 in a high vacuum.Because of possible decomposition, the '1.10-bis (2-diethylamino ethylmercapto)-decane should not be distilled. If desired, it can be madelighter, however, by treatment with activated charcoal and filtration.

8.09 parts of 1.IO-bis-(Z-diethylamino ethyl mercapto) decane in 70parts of dry acetone are heated to 50-60- with 3.4 parts by volume ofethyl iodide for 14 hours. After cooling, the product is filtered ofl bysuction and, if desired, recrystallised from acetone with the additionof a little abs. methanol. M. P. -132".

Wrasse Example 4 10.3 parts of 1.10-decane dithiole are dissolved in 53parts by volume of 50% caustic soda lye in a nitrogen atmosphere andthen 28 parts of 2-piperidino ethyl chloride hydrochloride are added inportions to the solution at 60 still in a nitrogen atmosphere.Thereafter the whole is stirred for 4 hours at 60 and for 2 hours at100. On cooling, the mixture is diluted with a little water, it isethered out and the ether solution is washed with a little water. Thebases are isolated by stirred with acid, etc., as described inExample 1. The raw base can be purified by way of the oxalate asfollows:

15.7 parts of the raw product are dissolved in a hot solution of partsof oxalic acid (+2H2O) in 125 parts by volume of water. On cooling, theacid oxalate of 1.10 bis (2 piperidino ethyl mercapto) decaneprecipitates from the clear solution as a thick paste. It is drawn offby suction, Washed with saturated aqueous oxalic acid solution, thenwith a little ice cold water and, if necessary, it can be recrystallisedto complete purity from water or alcohol. M. P. 196-198 ondecomposition.

On dissolving in hot water and adding cOnc. caustic soda lye to give analkaline reaction, the pure 1.10-bis- (2-piperidino ethyl mercapto)decane is precipitated and can be isolated by ethering out. It can beconverted in the usual way into other salts, e. g. the hydrochloride,the citrate or ethane disulphonate or into quaternary salts e. g. intothe metho-iodide (M. P. 170 from water), the ethobromide or methylmethosulphate.

The other tertiary and quaternary compounds listed in the descriptioncan also be prepared according to the processes described in the aboveexamples. Whenever it is possible to characterise the compounds bygiving the melting point or boiling point, this has been done.

6 What we claim is: 1. A diammonium compound of the formula wherein(Am)N represents a member selected from the group consisting of a lowerdialkylamino radical and a cyclic alkylene imino radical with 5 to 6ring members, Alk represents a lower alkyl group, and X is a monovalentanion selected from the group consisting of a halogen of a molecularweight of at least 35 and a lower monoalkylsulfate radical with 1 to 2carbon atoms, In is an integer from 2 to 3 inclusive, and n is aninteger from 10 to 12 inclusive.

2. The diamino compound of the formula:

(CH2) 1-0[SCH2CH2CH2N( C2H5) 3112 3. The diamino compound of theformula:

(CH2)1o[SCH2CH2N(CI-I3)2C4H9Br]2 4. The diamino compound of the formula:

5. The diamino compound of the formula:

(CH)2) 10[SCHzCH2-N(C2H5)3I]2 6. A diamino compound of the formulawherein alkylene contains from 2 to 3 carbon atoms, Hal is halogen of amolecular weight of at least 35, each of R1, R2 and R3 is lower alkyl,and R2 and R3 taken jointly with the N atom form a pyrrolidine radical.

References Cited in the file of this patent UNITED STATES PATENTS2,105,845 Reppe et al. Jan. 18, 1938 2,648,710 Morrison et al. Aug. 11,1953 2,659,756 Hafliger et al. Nov. 17. 1953 2,683,147 Girod July 6,1954 OTHER REFERENCES Walker: JCS (1950) pp. 193-97. Bovet: Annals, NewYork Acad. of Sciences, vol. 54,

0 art. 3, Oct. 30, 1951, p. 425.

J. Org. Chem., vol. 20, pp. -59 (1955). Price et al.: J. Org. Chem.,vol. 12, pp. 264-68 (1947).

1. A DIAMMONIUM COMPOUND OF THE FORMULA 